The purpose of this project is to increase our understanding of the interactions between the endocrine and immune systems in both experimental animals and humans. The stress hormones glucocorticoids and catecholamines inhibit the secretion of Interleukin(IL)-12 and stimulate the secretion of IL-10 by monocytes/macrophages, leading to a shift from Thelper1 to Thelper2-directed immunity. On the other hand, several immune system products, such as the cytokines Tumor Necrosis Factor-a (TNF-alpha), IL-1, and IL-6 activate the hypothalamic-pituitary-adrenal axis and through it suppress and restrain the inflammatory/immune response. Human fat examined in situ by microperfusion produces not only leptin, but also TNF-alpha and IL-6. The secretion of these cytokines has a circadian rhythm that is influenced by sleep while their circulating levels increase proportionally to the BMI and are furher elevated by visceral adiposity. We recently demonstrated that corticotropin-releasing hormone (CRH) is produced locally at sites of inflammation and has profound pro-inflammatory effects at an autocrine/paracrine level. CRH is a potent degranulator of mast cells, a phenomenon that can be inhibited by a nonpeptide CRH antagonist, specific for type 1 receptors called antalarmin. This antagonist has marked systemic anti-inflammatory actions. CRH was found in the ovary and endometrium where it may participate in the inflammatory phenomena of ovulation, luteolysis, blastocyst implantation, and menstruation. Antalarmin blocked implantation in rats and labor in sheep, suggesting that CRH antagonists may have clinical applications in reproductive medicine.